Skip to Content

Chemical News

The Further In You Go, The Bigger It Gets

I had a printout of the structure of maitotoxin on my desk the other day, mostly as a joke to alarm anyone who came into my office. “Yep, here’s the best hit from the latest screen. . .I hear that you’re on the list to run the chemistry end. . .what’s that you say?”
Maitotoxin
This is, needless to say, one of the largest and scariest marine natural product structures ever determined (and that determination has been no stroll past the dessert table, either).
But that’ hasn’t stopped people from messing around with it. And there’s much speculation that other people are strongly considering messing around with it, too – you synthetic chemists can guess the sorts of people that this might be, and their names, and what it might be like to sit through the seminars that result, and so on.
I fear that a total synthesis of maitotoxin would be largely a waste of time, but I’m willing to hear arguments against that position. Just looking at it, though, inspires thought. This eldrich beastie has 98 chiral centers. So let’s do some math. If you’re interested in the SAR of such molecules, you have your choice of (two to the 98th) possible isomers, which comes out to a bit over (3 times ten to the 29th) compounds. This is. . .a pretty large number. If you’re looking for 10mg of each isomer to add to your screening collection (no sense in going back and making them again), then you’re looking at a good bit over half the mass of the entire Earth. And that’s just in sheer compounds; we’re not counting the weight of vials, which will, I’d say, safely move you up toward the planetary weight of a low-end gas giant. We will ignore shelving considerations in the interest of time.
Recall that yesterday’s post gave a number of about 27 million compounds below 11 heavy atoms. You could toss 27 million compounds into a collection of ten to the 29th and never see them again, of course. But that brings up two points: one, that the small-compound estimate ignores stereochemistry, and we’ve been getting those insane maitotoxin numbers by considering nothing but. The thing is, with only 11 non-hydrogen atoms, there aren’t quite as many chances for things to get out of control. The GDB compound set goes up only to 110 million or so if you consider stereoisomers, which actually isn’t nearly as much as I’d thought.
But the second point is that this shows you why the Berne group stopped at 11 heavy atoms, because the problem becomes intractable really fast as you go higher. It’s worth remembering that the GDB people actually threw out over 98% of their scaffolds because they represented potential ring structures that are too strained to be very stable. And they only considered C, N, O and F as heavy atoms (even adding sulfur was considered too much to deal with, computationally). Then they tossed out another 98 or 99% of the structures that emerged from that enumeration as reactive and/or unstable. Relax your standards a bit, allow another atom or two, bump up the molecular weight, do any of those and you’re going to exceed anyone’s computational capacity. Update: the Berne group has just taken a crack at it, and managed a reasonable set up to 13 heavy atoms, with various simplifying assumptions to ease the burden. If you want to mess around with it, it’s here, free of charge).
No, there are a lot of compounds out there. And if you look at the really big ones – and maitotoxin is nothing if not a really big one – there are whole universes contained just in each of them. (Bonus points for guessing the source of the name of the post, by the way).

25 comments on “The Further In You Go, The Bigger It Gets”

  1. Anonymous says:

    alice in wonderland?

  2. schinderhannes says:

    Little, Big (John Crowly)

  3. Sychofish says:

    The Lion, the Witch and the Wardrobe?

  4. Katherine says:

    The Last Battle.

  5. Here’s a post about a JACS paper by the same group that developed GDB (11 million) now developing a version with almost 1 billion compounds, the largest until now.

  6. Derek Lowe says:

    Schinderhannes has it, in comment #2. An extremely odd book, that one.

  7. Tot. Syn. says:

    I’m torn as to whether it’s worth making or not. From a scientific / medicinal angle, the ends do not justify the cost. However, from a human-endeavour point of view, perhaps it has to be done. If (impossibly) a new mountain was discovered tomorrow, that was 10m taller than Everest, but had never been scaled, someone would have to do it. I think this might be a similar situation. I just hope the synthesis isn’t just Brevetoxin x 5…

  8. Chemjobber says:

    I agree with T.S. If it can be done in a novel fashion and not the brute force, hammer and tongs approach, it would be awesome.

  9. CMCguy says:

    From an industrial/practical standpoint such a massively complex target would seem of little value. However as eluded to by others it could be perhaps be an elegant demonstration of particular chemistry and a (further?) ego-enhancing inspiration in the power of synthetic chemistry.
    May be because I was trained in such labs that targeted natural products I have affinity (but not exclusively) for that type approach to learning/training even if counter to present operational mode. If nothing else it might get people acquainted with “team work” (which would be mandatory in this effort IMO) that can be lacking in most research groups. Hard to say what the real job market would be based on today’s dearth but anyone who successfully worked on such a beast would command at least some interest when comparing potential candidates.

  10. sjb says:

    Have you forgotten to close a tag somewhere? Lot of italic text today 😉

  11. milkshake says:

    if a monster like this turned out to be promising enough, a company would look into fermentation and semi-synthetic analoging

  12. Polymer Bound says:

    It’s a toxin… My understanding is that synthetic maitotoxin would be used to study its biology and potentially develop some sort of antidote to maitotoxin poisoning. I don’t think isolation yields useful quantities, although I would guess that optimizing its biological synthesis/isolation would be a faster approach to getting useful research quantities.

  13. Bob says:

    Considering that most of those chiral centers get set by ring-closing terpenes… 98 might matter as a d**k-measuring thing but from a biological standpoint it’s kind of a no-brainer.

  14. Process Guy says:

    Totally disagree with Bob – it would only be an exercise in measuring your junk if most of those 98 were the same, but they aren’t – some trans some cis, some ring fusions have a methyl, some do not. Stitching the thing together would be painful and loooooooong. 100% opposite of no-brainer.

  15. I hope the chemists who are synthesizing this baby are taking all the due care. I suspect even the intermediates would not be exactly benign.

  16. Anonymous says:

    @Curious Wavefunction:
    Exactly what I was wondering. I would not want to be anywhere near an academic department working on this synthesis. At what point do the guys in bunny suits have to take away your hplc columns?

  17. LiqC says:

    @15&16: these polyether compounds are usually carried forward in a protected form (read “big greasy gunk”), which is most certainly not active. Considering that only 77 micrograms of ciguatoxin (three times smaller than MTX) have been prepared, there is little reason to expect this project to be more dangerous than your everyday chores.

  18. Moody Blue says:

    Yes, synthesizing this beautiful beast is going to be one hellva task. But I must say I have always been very impressed by the folks who come up with structures of these complicated monsters with only tiny amounts!

  19. Evid Davans says:

    it is a prime chance for Nicolaou to get an erection
    Nothing will be achieved by making this compound, please stop

  20. non-pharma chemist says:

    I have to agree with “Evid Davans” on this one. All this molecule will do is make a small number of careers in academia and big pharma, for all the wrong reasons. Tenacity is only a virtue if it is pursuit of something worthwhile. CMCguy – in what pharmaceutical research area would such theoretical synthesizers of maitotoxin have an edge? Medchem or process? And why?

  21. Norepi says:

    I’m a little bit conflicted about this one myself. Perhaps synthesizing the godforsaken thing for purely academic pursuits would be ok (if not just a repeat of the decades-long Brevetoxin show)…but if anyone’s to do anything biological with it, some kind of actual “business end” of this molecule would have to be identified – presumably it acts by binding to voltage-gated sodium channels like ciguatoxin and ilk?

  22. CMCguy says:

    #20 non pharma chemist I was speculating but if wish to follow the hypothetical thread I was thinking its the mere involvement is such a complex venture that would likely garner greater attention. Unfortunately if you are looking through 200-300 (or more) Syn Chemist resumes in search for open positions (again talking fantasy realm) there is natural appeal to “interesting projects” to narrow the candidates (just like “name groups” often are). After that the specific person and work (vs the position) will have to stand-up to a deeper look but it may at least get person to the next level of consideration. Assumptions abound as I already mentioned possibility of team interaction aspect as positive and I disagree with your Tenacity comment (both that it would not be worthwhile pursuit academically and to demonstrate perseverance is a valuable attribute in med and process chem since will face much failure).

  23. Jose says:

    Once Kishi pooped out Brevetoxin, there are no new horizons in monster polyethers. Unless, of course, KCN’s ego can’t deal with not topping it….

  24. London Chemist says:

    Real molecule or isolation artefact? I still get suspicious about some of these…..

  25. Emilio says:

    Some links in this post (the first two, at least) are now broken.

Comments are closed.